The immunophilin ligands cyclosporin A and FK506 suppress prostate cancer cell growth by androgen receptor-dependent and -independent mechanisms

Sumudra Periyasamy, Manya Warrier, Manoranjani P M Tillekeratne, Weinian Shou, Edwin R. Sanchez

Research output: Contribution to journalArticle

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Abstract

The androgen receptor (AR) contributes to growth of prostate cancer even under conditions of androgen ablation. Thus, new strategies to target AR activity are needed. The AR interacts with the immunophilin FK506-binding protein 52 (FKBP52), and studies in the FKBP52 knockout mouse have shown that this protein is essential to AR activity in the prostate. Therefore, we tested whether the immunophilin ligand FK506 affected AR activity in prostate cancer cell lines. We also tested the hypothesis that the AR interacts with another immunophilin, cyclophilin 40 (Cyp40), and is regulated by its cognate ligand cyclosporin A (CsA). We show that levels of FKBP52, FKBP51, Cyp40, and a related co-chaperone PP5 were much higher in prostate cancer cells lines [(LNCaP), PC-3, and DU145] compared with primary prostate cells, and that the AR of LNCaP cells can interact with Cyp40. In the absence of androgen, CsA caused inhibition of cell growth in the AR-positive LNCaP and AR-negative PC-3 and DU145 cell lines. Interestingly, FK506 only inhibited LNCaP cells, suggesting a dependence on the AR for this effect. Both CsA and FK506 inhibited growth without inducing apoptosis. In LNCaP cells, CsA completely blocked androgen-stimulated growth, whereas FK506 was partially effective. Further studies in LNCaP cells revealed that CsA and FK506 were able to block or attenuate several stages of AR signaling, including hormone binding, nuclear translocation, and activity at several AR-responsive reporter and endogenous genes. These findings provide the first evidence that CsA and FK506 can negatively modulate proliferation of prostate cells in vitro. Immunophilins may now serve as new targets to disrupt AR-mediated prostate cancer growth.

Original languageEnglish
Pages (from-to)4716-4726
Number of pages11
JournalEndocrinology
Volume148
Issue number10
DOIs
StatePublished - Oct 2007

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Immunophilins
Androgen Receptors
Tacrolimus
Cyclosporine
Prostatic Neoplasms
Ligands
Growth
Tacrolimus Binding Proteins
Androgens
Prostate
Cell Line
Reporter Genes
Knockout Mice

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

The immunophilin ligands cyclosporin A and FK506 suppress prostate cancer cell growth by androgen receptor-dependent and -independent mechanisms. / Periyasamy, Sumudra; Warrier, Manya; Tillekeratne, Manoranjani P M; Shou, Weinian; Sanchez, Edwin R.

In: Endocrinology, Vol. 148, No. 10, 10.2007, p. 4716-4726.

Research output: Contribution to journalArticle

Periyasamy, Sumudra ; Warrier, Manya ; Tillekeratne, Manoranjani P M ; Shou, Weinian ; Sanchez, Edwin R. / The immunophilin ligands cyclosporin A and FK506 suppress prostate cancer cell growth by androgen receptor-dependent and -independent mechanisms. In: Endocrinology. 2007 ; Vol. 148, No. 10. pp. 4716-4726.
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